1. Field of the Invention
The present invention relates to a novel preparation method of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid represented by the following formula (1), a key intermediate of cilastatin used as a supplement to imipenem.

2. Description of the Prior Art
Conventional processes for the preparation of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid represented by the following formula (1) or its inorganic salt are described or mentioned in European Patent No. 48301, WO 2006/022511, and US Patent Application No. 2005/0119346.
According to the description in WO 2006/022511, ethyl(Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoate was mixed with (E)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ester (3), as shown in the following <Reaction Formula I>, at a ratio of about 85-90%: about 10-13% to prepare an isomer. The isomer mixture was then partially hydrolyzed with an alkali added at an amount less than equivalence to the titration, and a (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid alkali metal salt (aq) was extracted. The extracted salt was concentrated and purified by crystallization from an organic solvent.

However, this method is low in alkali-hydrolysis selectivity. Therefore, even though the hydrolysis was done with addition of an alkali at an amount less than equivalence to the titration, a considerable amount of (E) isomer and (Z) isomers are hydrolyzed together and an aqueous solution of an alkali salt being recovered, i.e., an aqueous solution of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid alkali metal salt, contains a substantial amount of the (E) isomers. To purify the solution, most of water was concentrated and removed, and a suitable organic solvent was added for crystallization. Unfortunately, purity of the resultant (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid alkali metal salt is very low, despite these strict conditions.
According to U.S. Pat. No. 5,147,868, in order to remove (E)-isomers, a (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid mixture containing a large amount of E isomers was used to prepare a cilastatin intermediate. This cilastatin intermediate was heated under acidic conditions for purification.
However, this method is disadvantageous in that hydrolysis following the heating operation under acidic conditions not only produced unknown impurities but also a respectable amount of the mixture was decomposed to (S)-2,2-dimethylcyclopropanecarboxamido which is very difficult to remove in practice. This is also mentioned in WO 2006/022511.
Therefore, there is a need to develop a new method for the preparation of (Z)-7-chloro-((S)-2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid of high purity in need of the efficient synthesis of cilastatin.